Early changes in interferon signaling define natural killer cell response and refractoriness to interferon-based therapy of hepatitis C patients

Hepatology. 2012 Jan;55(1):39-48. doi: 10.1002/hep.24628. Epub 2011 Nov 14.


Natural killer (NK) cells exhibit a polarized phenotype with increased cytotoxicity and decreased interferon gamma (IFN-γ) production in chronic hepatitis C virus (HCV) infection. Here, we asked whether this is caused by type I interferon (IFN)-induced expression and phosphorylation levels of signal transducer and activator of transcription (STAT) molecules in NK cells and whether it affects the response and refractoriness of NK cells to IFN-α-based therapy of HCV. STAT1 levels in NK cells were significantly higher in patients with chronic HCV infection than in uninfected controls. STAT1 levels and induction of phosphorylated STAT1 (pSTAT1) increased further during IFN-α-based therapy with preferential STAT1 over STAT4 phosphorylation. Induction of pSTAT1 correlated with increased NK cytotoxicity (tumor necrosis factor-apoptosis-inducing ligand [TRAIL] expression and degranulation) and decreased IFN-γ production. NK cells from patients with a greater than 2 log(10) first-phase HCV RNA decline to IFN-α-based therapy (>99% IFN effectiveness) displayed strong pSTAT1 induction in vivo and were refractory to further stimulation in vitro. In contrast, NK cells from patients with a less than 2 log(10) first-phase HCV RNA decline exhibited lower pSTAT1 induction in vivo (P = 0.024), but retained greater IFN-α responsiveness in vitro (P = 0.024). NK cells of all patients became refractory to in vivo and in vitro stimulation by IFN-α during the second-phase virological response.

Conclusion: These data show that IFN-α-induced modulation of STAT1/4 phosphorylation underlies the polarization of NK cells toward increased cytotoxicity and decreased IFN-γ production in HCV infection, and that NK cell responsiveness and refractoriness correlate to the antiviral effectiveness of IFN-α-based therapy.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Antiviral Agents / therapeutic use*
  • Cell Polarity / drug effects
  • Cell Polarity / immunology
  • Cohort Studies
  • Drug Resistance, Viral / immunology*
  • Female
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / immunology*
  • Humans
  • Interferon-alpha / therapeutic use*
  • Killer Cells, Natural* / immunology
  • Killer Cells, Natural* / metabolism
  • Killer Cells, Natural* / virology
  • Male
  • Middle Aged
  • Phosphorylation / immunology
  • Polyethylene Glycols / therapeutic use*
  • Prospective Studies
  • Recombinant Proteins / therapeutic use
  • Ribavirin / therapeutic use
  • STAT1 Transcription Factor / immunology
  • STAT1 Transcription Factor / metabolism
  • STAT4 Transcription Factor / immunology
  • STAT4 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • TNF-Related Apoptosis-Inducing Ligand / immunology
  • TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism


  • Antiviral Agents
  • Interferon-alpha
  • Recombinant Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT4 Transcription Factor
  • STAT4 protein, human
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • Polyethylene Glycols
  • Ribavirin
  • peginterferon alfa-2a